.beta.-hemoglobinopathies are a group of inherited disorders of .beta.-globin biosynthesis. Although efforts have concentrated on a variety of therapeutic regimens, feasible clinical treatments for these debilitating diseases remain scarce.
Various therapies have been utilized in the treatment of .beta.-hemoglobinopathies, each accompanied by drawbacks. G. P. Rogers et. al., "Current and Future Strategies for the Management of Hemoglobinopathies and Thalassemia", Hematology 1994, Education Program American Society of Hematology, pp. 9-20 (1994). Although the chemotherapeutic agent hydroxyurea stimulates fetal hemoglobin production and reduces sickling crisis in sickle cell anemia patients, its use is potentially limited by myelotoxicity and the risk of carcinogenesis. Potential long term carcinogenicity is also a drawback of 5-azacytidine-based therapies. Red blood cell transfusions expose patients to the potential of a wide range of infectious viral agents, as well as alloimmunization. Bone marrow transplants are not a readily available option for a large number of patients. Erythropoietin-based therapies have not proved consistent among a range of patient populations. Such varying drawbacks contraindicate the long term use of such agents or therapies.
It is clear from multicenter studies involving numerous patients with sickle cell disease that increased blood levels of fetal hemoglobin are associated with lower events of sickle cell crisis and longer survival time O. S. Platt et al., "Pain in Sickle Cell Disease, New Eng. J. Med., 325, pp. 11-16 (1991); O. S. Platt et al., "Mortality ion Sickle Cell Disease", New Eng. J. Med., 330, pp. 1639-44 (1994)!. Accordingly, in an effort to avoid the disadvantages of conventional therapies for .beta.-hemoglobinopathies, therapies have centered around ways to increase fetal hemoglobin production. Recent clinical trials have used butyrate analogs, including arginine butyrate and isobutyramide, to stimulate fetal hemoglobin production as a means of treatment S. Perrine et al., A Short Term Trial of Butyrate to Stimulate Fetal-Globin-Gene Expression in the .beta.-globin Disorders", N. Eng. J. Med., 328, pp. 81-86 (1993); S. P. Perrine et. al., "Isobutyramide, an Orally Bioavailable Butyrate Analogue, Simulates Fetal Globin Gene Expression In Vitro and In Vivo", British J. Haematology, 88, pp. 555-61 (1994); A. F. Collins et al., "Oral Sodium Phenylbutyrate Therapy in Homozygous .beta. Thalassemia: A Clinical Trial", Blood, 85, pp. 43-49 (1995).
Following the observation that butyric acid induces cell differentiation in vitro A. Leder and P. Leder, "Butyric Acid, a Potent Inducer of Erythroid Differentiation in Cultured Erythroleukemic Cells", Cell, 5, pp. 319-22 (1975)!, that compound was found to demonstrate promising effects in leukemia patients, by inducing cell differentiation A. Novogrodsky et al., "Effect of Polar Organic Compounds on Leukemic Cells", Cancer, 51, pp. 9-14 (1983)!. Aside from their use in treating .beta.-hemoglobinopathies, butyrate derivatives such as arginine butyrate, an arginine salt of butyric acid, have been shown to exert anti-tumor and anti-leukemia effects in mice C. Chany and I. Cerutti, "Antitumor Effect Of Arginine Butyrate in Conjunction with Corynebacterium Parvum and Interferon", Int. J. Cancer, 30, pp. 489-93 (1982); M. Otaka et al., "Antibody-Mediated Targeting of Differentiation Inducers To Tumor Cells: Inhibition of Colonic Cancer Cell Growth in vitro and in vivo", Biochem. Biophys. Res. Commun., 158, pp. 202-08 (1989)!.
Although butyrate salts have the advantage of low toxicity as compared with conventional chemotherapeutic agents, their short half-lives in vivo have been viewed as a potential obstacle in clinical settings A. Miller et al., "Clinical Pharmacology of Sodium Butyrate in Patients with Acute Leukemia", Eur. J. Clin. Oncol., 23, pp. 1283-87 (1987); Novogrodsky et al., supra!. The rapid clearance of these agents results in an inability to deliver and maintain high plasma levels of butyrate which necessitates administration by intravenous infusion. Another potential obstacle to the use of butyrate salts is salt overload and its physiological sequelae.
In view of these observations, various prodrugs of butyric acid have been proposed for use in .beta.-hemoglobinopathy and leukemia differentiation therapies. Such prodrugs include tributyrin and n-butyric acid mono- and polyesters derived from monosaccharides Z. Chen and T. Breitman, "Tributyrin: A Prodrug of Butyric Acid for Potential Clinical Application in Differentiation Therapy", Cancer Res., 54, pp. 3494-99 (1994); H. Newmark et al., "Butyrate as a Differentiating Agent: Pharmacokinetics, Analogues and Current Status", Cancer Letts., 78, pp. 1-5 (1994); P. Pouillart et al., "Pharmacokinetic Studies of N-Butyric Acid Mono- and Polyesters Derived From Monosaccharides", J. Pharm. Sci., 81, pp. 241-44 (1992)!. Such prodrugs have not proved useful as therapeutics, however, due to factors such as short half-life, low bioavailability, low C.sub.max, or lack of effective oral deliverability. Other prodrugs, such as AN-9 and AN-10 A. Nudelman et al., "Novel Anticancer Prodrug of Butyric Acid", J. Med. Chem., 35, pp. 687-94 (1992)!, elicit metabolites that may produce formaldehyde in vivo, leading to toxic effects in patients.
To date, conventional methods and therapeutic agents have not proved to be safe and effective for all patients in the treatment of .beta.-hemoglobinopathies. This is also the case for diseases characterized by neoplastic, tumorigenic or malignant cell growth, or malignant hematological disorders. Accordingly, the need exists for alternatives having advantages over, and avoiding the disadvantages of, such conventional methods and agents, while providing effective therapy for those target diseases.